tbuckley/cabot-search huggingface dataset:
How circulating cancer cells disguise: The role of platelets.
Authors: Dorothea Schott, Monika Pizon, Ulrich A. Pachmann, Erika Schill, Katharina Pachmann
Journal: Journal of Clinical Oncology (2022)

e15011 Background: Solid tumors are notorious for their ability to form lethal metastases, sometimes several decades following initial cancer diagnosis. Development of distant metastases is a result of the primary tumor shedding cells that travel via lymphatics and the blood to distant sites where they can form metastases. Platelets are known to specifically enhance tumor cells’ survival in the bloodstream by as yet poorly understood mechanisms. To study the interplay of platelets with circulating tumor cells, we implemented our published approach to label both circulating epithelial tumor cells and platelets. Methods: Blood samples were collected from 86 non-metastatic breast cancer patients avoiding fixation and processed at 4 time points following blood collection using the maintrac approach. Samples were additionally stained with anti-CD36 antibody to visualize platelets. Results: Typically, we observed at 0h post-blood draw platelet aggregates strictly attached to single cells that did not stain with anti-EpCAM antibody. These clogged unstained cells were, by far, outnumbered by surrounding white blood cells with no platelets attached. After keeping blood samples at room temperature for 24h a completely different picture became apparent: there were still cells detectable with platelets attached to them but the underlying cell now became accessible to the anti-EpCAM antibody leading to green fluorescence staining. CETCs were detected in 94% patients on day 1 post-blood draw. The increase in single platelets in the background could be a sign that after 24h, platelets detach from CETCs. At 72 h following initial blood drawing, platelets had almost completely disappeared from the cell surface. Numbers of EpCAM-positive cells remained stable between days 1 and 3. No CETCs were observed in 2 individuals with no cancer diagnosis, neither on day zero, nor on day 1. Conclusions: Our results suggest that platelets play a key role in masking circulating tumor cells. Masking may explain the difficulties in detection of these cells and prevention of their elimination by the immune system. Our unmasking approach detects sufficient numbers of circulating tumor cells to monitor the effect on blood tumor cells of different therapeutic measures, thus contributing to improved systemic therapies for cancer.
Radical versus local surgical excision for early rectal cancer: A systematic review and meta-analysis.
Authors: Sarah El-Nakeep, Samragnyi Madala, Anusha Chidharla, Benjamin Martin, Anup Kasi
Journal: Journal of Clinical Oncology (2022)

3622 Background: Colorectal cancer is the third common cancer worldwide. Radical excision (RE) as total mesorectal excision for rectal cancer carries a higher risk of mortality and morbidity, while local excision (LE) could decrease these postoperative risks. However, the long-term oncologic outcomes of LE are still debatable. We aim to study the effect of LE versus RE in T1 and T2 rectal cancer. Methods: We conducted a systematic review and meta-analysis. We searched PubMed and CENTRAL databases, using an optimized search-strategy from inception until 15 June 2021, without restriction on publication date or status. We included only cohort and randomized controlled trials (RCTs). Two authors independently screened the title, abstracts, and full-text manuscripts for inclusion and data extraction. All included trials contained at least one of the primary outcomes. We used RevMan 5.4 tool for data analysis. We calculated both hazards ratio (HR) and risk ratio (RR) for the 5-years survival analyses, with their 95% confidence intervals (CI). We assessed both clinical and statistical heterogeneity of the studies; I 2 &gt;75% was considered highly heterogeneous. We used random effect model (REM). We used standardized mean difference (SMD) for hospitalization days. We conducted a subgroup analysis of patients with T1-only without adjuvant chemo/radiotherapy (CRT). Results: We retrieved from the search a total of 1243 reports. A total of 18 studies were included for final meta-analysis (4 RCTs and 14 retrospective cohorts). Nine studies were multi-central while ten were unicentral studies. We did not find any difference in risk ratio (RR) between overall survival (OVS) and disease-free survival (DFS). But there were higher HRs in OVS and DFS with LE as compared to RE. A higher recurrence rate was also seen with LE. Six studies showed absent 30-days postoperative mortality in both groups so we used peto-odds ratio. Postoperative mortality and morbidity were lower with LE rather than RE. Conclusions: LE for early stage rectal cancer has a higher risk of decreased 5-year OVS and DFS than RE, with higher local recurrence rate. However, LE is associated with lower early postoperative mortality, morbidity, and hospitalization days, as compared to RE. Patient selection is key to balance these risks for the optimal outcome. [Table: see text]
Real-world treatment patterns and clinical outcomes with first-line therapy in cisplatin-eligible and ineligible patients with advanced urothelial carcinoma.
Authors: Guru P. Sonpavde, Matt D. Galsky, Phoebe Wright, Zsolt Hepp, Nancy N. Chang, Candice Willmon, Steven Sesterhenn, Yutong Liu, Alicia K. Morgans
Journal: Journal of Clinical Oncology (2022)

4565 Background: Advanced urothelial carcinoma (aUC) has a poor long-term prognosis. Despite new clinical trial data for novel therapies including PD-1/L1 inhibitors, data on real-world (RW) treatment patterns and overall survival (OS) in aUC patients (pts) treated with first line (1L) therapy are limited. Methods: This retrospective observational study describes the contemporary RW 1L treatment patterns and OS in aUC pts stratified by cisplatin (cis)-eligibility (based on accepted criteria) and treatment. Data were from the nationwide Flatiron Health longitudinal electronic health record-derived database, comprising de-identified patient-level structured and unstructured data. Eligible pts were adults diagnosed with aUC from May 2016-Oct 2020 and followed until death or end of data availability in July 2021. OS was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. Results: Of 4,300 aUC diagnosed pts, 3,311 (77.0%) received 1L treatment; 1836 (55.5%) cis-ineligible, 1475 (44.5%) cis-eligible. Differences between cis-ineligible and cis-eligible pts were observed, with cis-ineligible more likely to be older (mean age, 75.0 vs 69.0 yrs), have lower CrCl (median, 45.3 vs 80.7 mL/min), and worse ECOG-PS (2+, 29.2 vs 0%). Only 44.4% received 2L therapy: 38.3% cis-ineligible vs 52.0% cis-eligible. Median OS in all 1L treated pts was 11.0 (95% CI, 10.3 – 11.5) mo and was shorter in cis-ineligible than cis-eligible pts (8.6 [95% CI, 8.1 – 9.2] vs 14.4 [95% CI, 13.4 – 16.4]; hazard ratio [HR], 0.8 [0.7 – 1.0]). A number of cis-ineligible pts received cis, and many cis-eligible pts did not (Table), suggesting physicians consider clinical factors beyond conventional criteria to determine cis-eligibility. Cis + gemcitabine (gem) or MVAC was associated with longer OS vs other treatments regardless of cis-eligibility (Table). Conclusions: Clinical outcomes in 1L aUC pts were poor, particularly for cis-ineligible pts, which may be partly driven by the specific regimen administered. Many aUC pts did not receive 1L treatment and among those who did, less than half received 2L therapy. These data highlight the need for more effective and tolerable 1L therapy for all aUC pts. [Table: see text]
The landscape of <i>ACVR2A </i>mutations in Chinese solid tumor patients.
Authors: Xin Li, Yaoyao Ren, Caifeng Li, Cui Luo, Juan Ma, Zhengying Bian, Minghui Ge, Guanghua Lu, Ran Ding, Fanfeng Bu
Journal: Journal of Clinical Oncology (2022)

e14523 Background: ACVR2A (activin A receptor type 2A) encodes a receptor that mediates the functions of activins, and it contains two polyadenine (A8) microsatellite loci, which are located in exon 3 and exon 10. Recent studies have shown that ACVR2A mutant was associated with microsatellite instability-high (MSI-H) and high tumor mutational burden(TMB-H) in gastrointestinal cancers. However, this association remains unclear in other solid tumors. Methods: We retrospectively analyzed the ACVR2A mutations from comprehensive 539-gene profiling of 10434 Chinese patients with pan-cancer. Somatic mutations in tumor tissue were assessed. We screened out ACVR2A mutations, calculated the mutation frequency, TMB in different types of cancer. Results: ACVR2A mutants were detected in 340 (2.9%) samples. The top 5 frequently cancers were colorectal cancer (98, 28.8%), lung carcinoma (68, 20%), hepatocellular carcinoma (64, 18.8%), gastric cancer (48, 14.1%) and biliary tract cancers (19, 5.6%). And 12.7% were other cancers (e.g., pancreatic cancer, small bowel adenocarcinoma, brain cancer). ACVR2A variants included truncation (50%), splicing site variant (9.0%), and other mutant types(41.1%). Truncation was the most common type, recurring in a few hot spots (K437Rfs*5/ K437Rfs*19, D96Tfs*54/ D96Rfs*4, V433del, R438Efs*19). The TMB in ACVR2A mutation group was significantly higher than that in ACVR2A wild-type group (p &lt; 0.001). In addition, TMB ≥10 muts/Mb was seen in 76.7% tumors with ACVR2A truncation or splicing site mutant(INACT) and 20.6% tumors with other mutant types(VUS)(p = 0.002). The median TMB of INACT group and VUS group was 35.46 muts/Mb (0.74-344.12) and 6.62 muts/Mb(0.5-598.53), respectively. Conclusions: We analyzed the distribution of ACVR2A mutants in Chinese patients with solid tumors. Our data shows that ACVR2A truncation or splice site mutant type is significantly associated with TMB-H, and this may be potential molecular marker of immunotherapy.
IBI110 (anti-LAG-3 mAb) as a single agent or in combination with sintilimab (anti-PD-1 mAb) in patients with advanced solid tumors: Updated results from the phase Ia/Ib dose-escalation study.
Authors: Nong Xu, Chenyu Mao, Jiong Qian, Yulong Zheng, Haiping Jiang, Yuan Gao, Cheng Xiao, Anwen Xiong, Wei Li, Yayi He, Shengxiang Ren, Lei Wang, Jia Yu, Jun Zhu, Ying Liu, Caicun Zhou
Journal: Journal of Clinical Oncology (2022)

2650 Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. A phase Ia/Ib dose-escalation study evaluated IBI110 ± sintilimab in patient with advanced solid tumors; initial efficacy and safety data were previously presented (C Zhou et al. ASCO 2021; NCT04085185). Here, we reported the updated results. Methods: Eligible patients were ECOG PS 0-1 and had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Patients received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5/8/10 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from monotherapy to combination therapy was allowed at progression. The primary objectives were safety, tolerability, and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 28 patients (median age of 60.5 years [range 35-72], ECOG PS of 0 [n = 14] and 1 [n = 14]) were enrolled. Dose escalation was completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The safety profile was generally consistent with the initial. By investigator-assessment, best response was 1 confirmed partial response (PR) and 6 stable diseases (SD) with monotherapy. After crossing to combination therapy at progression, 8 patients who failed prior anti-PD-(L)1 mAb therapy achieved SD. Phase Ib: Overall, 45 patients (median age: 60.0 yr [range 33-74]; ECOG PS: 0 [n = 14], 1 [n = 31]) were enrolled in all dose levels. Dose escalation was completed and no DLT was observed. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (28.9%), anaemia (24.4%), and alanine aminotransferase increased (22.2%). TRAEs ≥ grade 3 occurred in 10 (22.2%) patients. Immune-related AE (irAE) incidence was 31.1%, and the most common irAE was hypothyroidism (15.6%). In 43 patients who had undergone at least 1 post-baseline tumor assessment, the investigator-assessed best response included 6 PRs (1 endometrial cancer, 4 NSCLC, and 1 SCLC patients) and 23 SDs. Three patients showed a progression-free survival &gt; 1 year and continued treatment. Conclusions: IBI110 alone or plus sintilimab demonstrated acceptable safety profile and promising antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04085185.
Malignant pleural mesothelioma in Brazil: An analysis of public databases between 2000 and 2017.
Authors: Guilherme Jorge Costa, Isabella Favato Barcelos, Gabriela Monte Tenorio Taveira, Pedro De Marchi, Tatiane Caldas Montella, Luiz Claudio Santos Thuler, Carlos G. M. Ferreira
Journal: Journal of Clinical Oncology (2022)

e20597 Background: malignant mesothelioma is a rare tumor with about 31,000 new cases diagnosed annually worldwide. Malignant pleural mesothelioma (MPM) is recognized as an occupational cancer, and past exposure to asbestos represents its main risk factor. Little is known about the epidemiological and clinicopathological profile in developing countries. Methods: this is a cross-sectional study that analyzed the incidence and mortality rates and the clinicopathological profile of MPM in Brazil, from Brazilian public databases: Population-Based Cancer Registries (PBCRs - for incidence), Hospital Cancer Registry (HCR - for clinicopathological profile) and National Mortality Information System (SIM - for mortality). Results: In thirty PBCRs, from 23 of 26 states (average covered of 17% of the Brazilian population), 310 new MPM cases were reported, from 2000 to 2015. The mean age at diagnosis was 62.8 years. Incidence crude rate reached its maximum of 8.96 per 1.000.000 men in the 75-79 age group, and of 3.34 per 1.000.000 women in the 80+ age group. The clinicopathological profile registered in the HCR, from 2000 to 2017, showed a majority of men (70.2%), smoker/former smoker (62.7%) and alcohol users (58.2%). Regarding histology, 59% were described as mesothelioma, NOS (not otherwise specified), 30.6% as epithelioid, 7% as fibrous mesothelioma and 3.4% as biphasic. 54.4% were stage IV at diagnosis, 27.5% stage III and 18.1% stages I or II. A quarter of the patients received neither local nor systemic treatment. From 2000 to 2017 512 deaths related to MPM were registered in SIM database, an average of 28 deaths per year (mean age of death 63.7 years). The age-adjusted mortality rate remained statistically stable over all analyzed period. Conclusions: According to our study, most MPM patients in Brazil are elderly men, stage IV at diagnosis, with mesothelioma NOS. A considerable percentage do not receive any specific treatment for the disesase. Understanding the scenario of MPM in Brazil is important to design prevention, diagnosis and treatment strategies.
Reliable determination of genetic ancestry from cancer-derived molecular data.
Authors: Pascal Belleau, Astrid Deschênes, David A. Tuveson, Alexander Krasnitz
Journal: Journal of Clinical Oncology (2022)

e13588 Background: There is ample epidemiological evidence that, for multiple cancer types, incidence, stage at presentation and outcome correlate strongly with the patient’s race or ethnicity. Recent examination of cancer data repositories such as TCGA has revealed has revealed, for a number of cancers, ancestry dependence of somatic mutation spectrum and transcriptional phenotype. Further progress in genetic ancestry-oriented cancer research requires the ability to perform accurate and robust ancestry inference from existing cancer-derived data, including whole exomes, transcriptomes and targeted gene panels, very often in the absence of matching cancer-free genomic data. Such inference is potentially challenging, given widespread somatic alterations in tumor genomes, observed in multiple types of cancer. Methods: In order to optimize and assess the performance of the ancestry inference for any given input cancer-derived molecular profile, we develop a data synthesis framework. In its core procedure, the ancestral background of the profiled patient is replaced with one of any number of individuals with known ancestry. We then infer the substitute individual’s ancestry, using well-established methods of population genetics and relying on the 1000 Genomes collection as a population reference data set. Data synthesis is applicable to multiple profiling platforms and makes it possible to assess the performance of inference specifically for a given molecular profile, and separately for each continental-level ancestry. This ability extends to all ancestries, including those without statistically sufficient representation in the existing cancer data. Results: We test our approach for three representative cancer types: pancreatic and ovarian cancers as representative of epithelial tumor types, and acute myeloid leukemia as an example of hematopoietic malignancy. We consider tumor-derived data acquired by the whole-exome sequencing, by exome sequencing restricted to a panel of cancer-associated genes, and by RNA sequencing. For all three cancer types, and across the three sequencing platforms, we demonstrate that global, continental-level ancestry of the patient can be inferred accurately and robustly. Specifically, we find the inferred ancestries to be in at least 97% agreement with the golden standard of the ancestry derived from the matching cancer-free genomes. We further show that our inference procedure is accurate and robust in a wide range of sequencing depths. Conclusions: Our study demonstrates that vast amounts of existing cancer-derived molecular data are amenable to ancestry-oriented studies of the disease, without recourse to matching cancer-free genomes or patients' self-identification by ancestry. Furthermore, the procedure we developed facilitates ancestry-oriented research using archived tumor tissue specimens, for which matching cancer-free specimens may not be available.
RC48-ADC for metastatic urothelial carcinoma with HER2-positive: Combined analysis of RC48-C005 and RC48-C009 trials.
Authors: Xinan Sheng, Zhisong He, Yanxia Shi, Hong Luo, Weiqing Han, Xin Yao, Benkang Shi, Jiyan Liu, Changlu Hu, Ziling Liu, Hongqian Guo, Guohua Yu, Zhigang Ji, Shiying Yu, Yi Hu, Jianming Guo, Jianming Ying, Jianmin Fang, Aiping Zhou, Jun Guo
Journal: Journal of Clinical Oncology (2022)

4520 Background: RC48-ADC (Disitamab Vedotin) is a novel humanized anti-HER2 antibody-drug conjugate (ADC). RC48-ADC demonstrated a promising efficacy with a manageable safety profile in HER2-positive locally advanced or metastatic UC patients who failed to platinum based chemotherapy in RC48-C005 and RC48-C009 trials. Here are the pooled results of the two studies with the supplementary efficacy, safety and updated OS data. Methods: Both of the two trials are single-arm, multi-center, phase II trials. Eligible patients were 18̃80 years old, with central-laboratory confirmed, histologically HER2-postive (IHC2+,3+), unresectable mUC. Patients had at least one line of systemic chemotherapy. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety were also assessed. Results: RC48-C005 and RC48-C009 enrolled HER2-positive locally advanced or metastatic UC patients from Nov 2017 to Sep 2020. 107 mUC patients (80 males; median age 63 y [40-79]) were enrolled. 64.5% patients had received ≥ 2 lines systemic chemotherapy. 90.7% patients had visceral metastases. As of 04 Sep 2021 (data cutoff), The overall confirmed ORR as assessed by the BIRC was 50.5% (95% CI: 40.6%, 60.3%). Similar responses were observed in prespecified subgroups. cORR was 52.1% (25/48) for patients with liver metastasis and was 55.6% (15/27) in patients with previous PD-1/L1 treatment. The cORR was 62.2% (28/45) for HER2 IHC2+&amp;FISH+ or IHC3+ patients, 55.6% (5/9) for HER2 IHC2+&amp;FISH unknown patients, and 39.6% (21/53) for HER2 IHC2+&amp;FISH- patients respectively. DCR was 82.2% (95% CI:73.7%, 89.0%). The mPFS was 5.9 (95% CI:4.2, 7.2) months. The mOS was 14.2 (95% CI:9.7, 18.8) months. The median OS follow up time was 19.1 months. Most common treatment-related AEs were hypoaesthesia (50.5%), Leukopenia (49.5%), aspartate aminotransferase increased (43.0%), neutropenia (42.1%), alopecia (40.2%), asthenia (39.3%), alanine aminotransferase increase (35.5%), decreased appetite (31.8%). The grade ≥3 TRAEs (≥5%) only included hypoaesthesia (15.0%), neutropenia (12.1%) and r-GT increased (5.6%). Conclusions: RC48-ADC showed continuously a promising efficacy with a manageable safety profile in HER2-postive mUC patients who had failed at least one line systemic chemotherapy. Clinical trial information: NCT03507166, NCT03809013.
Single cell transcriptomic characterization of natural killer (NK) cell populations in clear cell renal cell carcinoma and association with clinical outcomes.
Authors: Wenxin Xu, Maheetha Bharadwaj, Grace Birch, Nicholas Schindler, Chris Labaki, Renee Maria Saliby, Ziad Bakouny, Dory Freeman, Jillian O'Toole, Gwo-Shu Mary Lee, Bradley Alexander McGregor, Michelle S. Hirsch, Sachet A. Shukla, David F. McDermott, Sabina Signoretti, Rizwan Romee, Toni K. Choueiri, David A. Braun
Journal: Journal of Clinical Oncology (2022)

e16521 Background: Natural killer (NK) cells are thought to play a key role in the immune response against cancer, including clear cell renal cell carcinoma (ccRCC). However, the transcriptomic landscape of NK cells in ccRCC and the mechanisms of NK cell evasion by ccRCC are poorly understood. Methods: We analyzed scRNA-sequencing (10x Genomics) data from tumor specimens and adjacent non-tumor tissue from ccRCC at various clinical stages. Clustering analysis and NK cell lineage markers were used to identify distinct NK cell populations. Differential gene expression analysis was used to characterize each cluster compared to the total population of NK cells. Results were correlated with clinical stage. Gene signatures, derived from NK cell subclusters of interest, were then used to interrogate bulk transcriptomic datasets and associate expression with clinical outcomes. Results: Single-cell RNA-sequencing data was analyzed from 13 patients, corresponding to &gt; 23,000 individual NK cells. Clustering analysis revealed 11 distinct NK cell subsets, including two “resident” NK cell clusters that were enriched among patients with metastatic disease. These clusters expressed CD9, ITGA1/CD49a, and ITGAE/CD103. Further examination of these clusters showed a common panel of differentially expressed genes, including decreased expression of cytotoxicity markers and upregulation of inhibitor checkpoints such as KLRC1/NKG2a. A gene expression signature representing this resident NK cell phenotype was associated with worse overall survival in two large, independent patient cohorts (TCGA and CheckMate-025). Conclusions: Among patients with ccRCC, a retrospective single cell transcriptomic analysis revealed heterogeneous NK cell populations. A seemingly dysfunctional, “resident” NK cell phenotype is enriched among patients with metastatic disease and is associated with worse survival in patients with advanced ccRCC, including those treated with immune checkpoint inhibitors. Restoration of NK cell function could be a future therapeutic opportunity among patients with ccRCC.